The broad aims of this project are to investigate the molecular mechanisms underlying insulin action in mammalian cells. Apparent differences between normal and transformed cells in insulin sensitivitiy of intracellular protein degradation are used as the experimental model. Rates of protein breakdown in a variety of different transformed cells are much more sensitive to insulin inhibition. This effect is rapid and occurs with a lag-time less than or equal to 30 mins. It appears to require the presence of specific insulin receptors but is not due to differences in the affinity nor the number of receptors, nor is it due to changes in the rate of insulin degradation. In general, these findings apply also to other mitogenic polypeptide factors such as epidermal growth factor, fibroblast growth factor, and the insulin-like growth factors, IGF-I and II. We intend to investigate other aspects of insulin action, such as protein synthesis and lactate production, to compare the effects of insulin analogs on protein breakdown and to investigate the putative role of hormone-receptor clustering, internalization, and hormone degradation in insulin action.